Biology subjects

Habiel, D. M.

Publications and source records attributed to Habiel, D. M..

2 recordsLinked to original sources

bioRxiv2019

Targeting Lysyl oxidase-like 2 in Idiopathic Pulmonary Fibrosis

The composition of extracellular matrix (ECM) is altered during pathologic scarring in damaged organs including the lung. One major change in the ECM involves the cross-linking of collagen, which promotes fibroblast to myofibroblast differentiation.\n\nObjectiveWe examined the role of lysyl oxidase (LOX)-like 2 in lung fibroblasts cultured from normal or IPF lung samples and in a humanized mouse model of IPF using a monoclonal antibody (Simtuzumab).\n\nResearch Design and MethodsPrimary lung fibroblasts from normal donor lungs and IPF lung explants were examined for expression of LOXL2. Targeting LOXL2 with Simtuzumab on normal and IPF fibroblasts was examined both in vitro and in vivo for synthetic, functional, and profibrotic properties.\n\nResultsLOXL2 was increased at transcript and protein level in IPF compared with normal lung samples. In a dose-dependent manner, Simtuzumab enhanced differentiation of fibroblasts into myofibroblasts. Inhibition of LOXL2 also enhanced fibroblast invasion and accelerated the outgrowth of fibroblasts from dissociated human lung cell preparations. Finally, preventative or delayed delivery of Simtuzumab enhanced lung fibrosis in a humanized mouse model of pulmonary fibrosis.\n\nConclusionConsistent with its failure in a Phase 2 clinical trial, Simtuzumab exhibited no therapeutic efficacy in translational in vitro and in vivo assays.

cell biology↗

bioRxiv2017

Role of Immune Checkpoint Proteins in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease, with unknown etiopathogenesis and suboptimal therapeutic options. Due to the lack of clinical efficacy of standard immuno-suppressants in IPF, the role of the immune response in this disease remains elusive. Nevertheless, previous reports have shown that increased T cell numbers and phenotype is predictive of prognosis in IPF, suggesting that these cells might have a role in this disease. Transcriptomic analysis of CD3+ T cells isolated from IPF lungs removed prior to lung transplant (i.e. explant lung) revealed a loss of CD28 expression and both elevated checkpoint and lymphocyte activation pathways. Flow cytometric analysis of a mixture of immune and non-immune cells isolated from explanted IPF lungs showed elevated PD-1 and CTLA4 protein expression on CD4- lymphocytes and PD-L1 expression on EpCAM+ and CD45- EpCAM- cells. Lung remodeling and loss of BAL surfactant protein C were observed in NOD SCID IL-2R{gamma}-/- (NSG) mice that received an intravenous injection of a mixture of IPF cells, including purified IPF T cells. Finally, in humanized NSG mice, anti-CTLA4, but not anti-PD1, mAb treatment induced an expansion of CD3+ T cells and accelerated lung fibrosis. Together, these results demonstrate that IPF T cells are profibrotic but the immune checkpoint protein, CTLA-4, appears to limit this effect in IPF.

immunology↗